Effect of solvent and ancillary ligands on the catalytic H/D exchange reactivity of Cp IrIII(L) complexes

Article abstract of DOI:10.1021/cs400420n

The reactivity of a series of Cp*lIr^III(L) complexes that contain a diverse set of ancillary ligands, L, (L = PMe₃, N-heterocyclic carbene, NHC = 1,3-dimethylimidazol-2-ylidene, aqua, 4-t-butylpyridine, and 4-(2,4,6-tris-(4-t-butylphenyl)pyridinium)pyridine tetrafluoroborate) has been examined in catalytic H/D exchange reactions between C₆H₆ and a series of deuterated solvents (methanol-d ₄, acetic acid-d₄, and trifluoroacetic acid-d ₁). These studies demonstrate that (1) the mechanism of catalytic H/D exchange is significantly influenced by the nature of the solvent; (2) electron-donating ligands (PMe₃, NHC) promote the formation of Ir hydrides in methanol-d₄, and these are critical intermediates in catalytic H/D exchange processes; and (3) weak/poorly donating ligands (4-t-butylpyridine, 4-(2,4,6-tris-(4-t-butylphenyl)pyridinium)pyridine tetrafluoroborate and aqua) can support efficient H/D exchange catalysis in acetic acid-d₄.

Full text of DOI:10.1021/cs400420n

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Article
Effect of Solvent and Ancillary Ligands on the Catalytic
H/D Exchange Reactivity of Cp*IrIII(L) Complexes.
Matthew C. Lehman, John Brannon Gary, Paul D. Boyle, Melanie S. Sanford, and Elon A. Ison
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/cs400420n • Publication Date (Web): 27 Aug 2013
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Effect of Solvent and Ancillary Ligands on the
Catalytic H/D Exchange Reactivity of Cp*IrIII(L)
Complexes.
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Matthew C. Lehman†, J. Brannon Gary‡, Paul D. Boyle†, Melanie S. Sanford‡ and Elon A. Ison†*
†Department of Chemistry, North Carolina State University, 2620 Yarbrough Drive, Raleigh, NC
27695-8204 and ‡Department of Chemistry, University of Michigan, 930 N. University Avenue,
Ann Arbor, Michigan 48109.
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KEYWORDS. H/D Exchange. C-H Activation. C-H Functionalization. Cp*IrIII catalysts.
Kinetics. Isotope Effects.
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ABSTRACT. The reactivity of a series of Cp*IrIII(L) complexes that contain a diverse set of
ancillary ligands, L, (L = PMe3, N-heterocyclic carbene, NHC = 1,3-dimethylimidazol-2-ylidene,
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aqua,
4-t-butylpyridine,
and
4-(2,4,6-tris-(4-t-butylphenyl)-pyridinium)pyridine
tetrafluoroborate) has been examined in catalytic H/D exchange reactions between C6H6 and a
series of deuterated solvents (methanol-d4, acetic acid-d4 and trifluoroacetic acid-d1). These
studies demonstrate that: (1) The mechanism of catalytic H/D exchange is significantly
influenced by the nature of the solvent; (2) Electron-donating ligands (PMe3, NHC) promote the
formation of Ir hydrides in methanol-d4, and these are critical intermediates in catalytic H/D
exchange processes; and (3) Weak/poorly donating ligands (4-t-butylpyridine, 4-(2,4,6-tris-(4-t-
butylphenyl)-pyridinium)pyridine tetrafluoroborate and aqua) can support efficient H/D
exchange catalysis in acetic acid-d4.
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INTRODUCTION
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Iridium complexes have been shown to be highly effective for the stoichiometric
activation of C-H bonds. In particular, extensive work by Bergman and coworkers has provided a
detailed mechanistic picture of stoichiometric C-H activation reactions at Cp*Ir(I) and Cp*Ir(III)
complexes.1 Despite these pioneering studies, it has, until recently, remained challenging to
exploit the facile C–H activation abilities of Cp*Ir complexes in catalytic C–H functionalization
reactions. In contrast, [Cp*Rh] complexes have been shown to catalyze a wide variety of
different ligand-directed C–H functionalization reactions.2 For example, Glorius et al recently
demonstrated [Cp*RhCl2]2-catalyzed C–H activation/halogenation sequences.2c To date, C–H
functionalization of arenes and alkanes with the Cp*Ir fragment remains underdeveloped.
Some of us have recently reported the Ir-catalyzed synthesis of benzochromenones from
benzoic acids and alkynes.3 In addition, Crabtree and coworkers have demonstrated the
hydroxylation of C-H bonds catalyzed by a series of Cp*Ir complexes.4 The mechanisms for
many of these transformations are still not established. Further, a detailed understanding of the
factors that lead to efficient catalytic C-H functionalization with Cp*Ir complexes is needed in
order to rationally design new catalysts and catalytic transformations.
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H/D exchange reactions between C6H6 and deuterated solvents have been utilized recently
to study C-H activation.5 This method has the advantage that it does not depend on the isolation
of transient organometallic complexes; furthermore, the reaction is believed to proceed via
intermediates that are directly relevant to catalytic C-H functionalization reactions. In this
Article, we compare the reactivity of a series of Cp*IrIII(L) complexes that contain a diverse set
of ancillary ligands, L, (L = PMe3, N-heterocyclic carbene, NHC = 1,3-dimethylimidazol-2-
ylidene, aqua, 4-t-butylpyridine, and 4-(2,4,6-tris-(4-t-butylphenyl)-pyridinium)pyridine
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tetrafluoroborate) in catalytic H/D exchange reactions between C6H6 and a series of deuterated
solvents (methanol-d4, acetic acid-d4 and trifluoroacetic acid-d1). These studies lead us to three
key conclusions about C–H activation at Cp*Ir complexes: 1) The mechanism of catalytic H/D
exchange is significantly influenced by the nature of the solvent; 2) Electron-donating ligands
(PMe3, NHC) promote the formation of Ir hydrides in methanol-d4, and these species serve as
intermediates in catalytic H/D exchange reactions; and (3) Weak/poorly donating ligands (4-t-
butylpyridine, 4-(2,4,6-tris-(4-t-butylphenyl)-pyridinium)pyridine tetrafluoroborate and aqua)6
can support efficient H/D exchange catalysis in acetic acid-d4. Overall, this work shows that by
controlling the reaction conditions and the ancillary ligands coordinated to the metal we can
dramatically influence C-H activation reactivity. Since complexes featuring the Cp*Ir(L) motif
have been shown to be among the most effective in stoichiometric C-H activation reactions, the
results presented here have significant potential implications for the development of C-H
functionalization catalysts.
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RESULTS AND DISCUSSION
The Cp*IrIII(L) complexes that were examined in the current study are depicted in Chart 1. The
catalysts can be broadly separated into two categories: 1) Complexes incorporating strong donor
ligands (PMe3 and NHC); and 2) Complexes incorporating weak donor ligands (H2O, pyridine
derivatives). Notably, the diiridium hydride (5) was obtained by heating 4 in MeOH and was
characterized by NMR spectroscopy and X-ray crystallography (Figure 1). The structure of 5 is
similar to a related complex reported by Yamaguchi and coworkers, where the tetramethyl-
substituted NHC ligand was utilized (NHC = 1,3,4,5-tetramethylimidazol-2-ylidene).7 The bond
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distance between the two Ir centers in 5 is 2.7118(6) Å. The geometry at each metal center is best
described as a three-legged piano stool.
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Chart 1. Catalysts used in this study.
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Complexes incorporating strong donor ligands
OTf2
OTf2
N
H
H
N
Ir
Ir
Ir
Ir
OH2
OH2
Cl
Ir
N
N
N
Cl
Cl
Me3P
Cl
N
N
N
5
1
4
3
Complexes incorporating weak/poor donor ligands
OTf2
BF4
BF4
Ir
Ir
Cl
Cl
Ir
Cl
OH2
OH2
N
N
H2O
Cl
Ar
6
2
7
N
t-Bu
Ar
Ar
Figure 1. X-ray crystal structure of complex 5. Ellipsoids are at the 50% probability level.
Hydrogen atoms and triflate counterions were omitted for clarity. Selected bond lengths (Å)Ir1-
Ir2, 2.7118(6); Ir1-C1, 2.0266(18); Ir2-C6, 2.0238(18).
The syntheses of all of the catalysts utilized in this work are described in detail in the
Supporting Information. Complexes 1-4 were previously examined as catalysts for H/D
exchange reactions but have not been compared under the same conditions or studied
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mechanistically.8 Further, while many of these complexes have been examined for H/D
exchange, the mechanisms of these reactions have not been systematically investigated. In
particular, the role of solvents and ancillary ligands on catalytic H/D exchange reactivity has not
been probed.
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H/D Exchange Reactions.
Deuterium incorporation into C6H6 was examined for complexes 1-7. A general reaction is
shown in Scheme 1 with methanol-d4, acetic acid-d4, and trifluoroacetic acid-d1 chosen as
solvents and deuterium sources. Deuterium incorporation and turnover numbers (TONs) were
determined by GC/MS utilizing a quantitative assay.5d
Scheme 1. Ir-catalyzed H/D exchange
2 mol% Ir
dn
d-Source
150 ºC
d-Source = acetic acid-d4, methanol-d4, triflouroacetic acid-d1
a. Reactions in Methanol-d4. The results of studies with methanol-d4 are shown in Table 1.
Catalyst 1 when treated with AgOTf (entry 2), 4 (entry 6), and 5 (entry 7), showed the highest
activity for H/D exchange. When 3 was treated with AgOTf (entry 5), the activity increased
approximately five-fold compared to the reaction of 3 without additive (entry 4). This suggests
that AgOTf abstracts the chloride ligands in 3 to generate a more active catalyst. This effect is
even more pronounced for 1, as the TONs increase by more than an order of magnitude upon
addition of AgOTf (entries 1 and 2). It is also important to note that in this solvent H/D AgOTf
does not catalyze exchange, and H/D exchange does not take place without an Ir catalyst.
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Table 1. Results for catalytic H/D exchange reactions with complexes 1-7 in methanol-d4.a
5
6
7
Entry
Catalyst Additive TONb
8
9
1
2
3
4
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10
1
1
2
3
3
4
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None
11(3)
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AgOTfc 179(3)
None
None
16.5(2)
9.3(4)
AgOTfc 44(9)
None
None
None
79(5)
76(6)
NDd
AgOTfc 3(0)
None 7(3)
AgOTfc 3(2)
11
a
Reactions were run for 24 h with 25
equivalents of deuterium source to C6H6.b
Reported turnover numbers are the
average of at least three trials and error is
reported as the standard deviation of the
mean. Turnover numbers (TONs) are
calculated as moles of D incorporated per
mole of catalyst. Conditions: Benzene-d6
(42 μL, 0.475 mmol), methanol-d4 (11.9
mmol), and the respective iridium(III)
c
catalyst (0.0095 mmol). Two equivalents
of AgOTf were added. No deuterium
incorporation was detected.
d
The TONs achieved with catalysts 4 and 5 (entries 6 and 7) are comparable. This is
consistent with the observation that 5 is the major species in methanol when 4 is employed as the
catalyst in H/D exchange reactions. Notably, complexes that contain moderate/weak donor
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ligands (H2O, 2; pyridine, 6; pyridinium, 7) exhibit poor reactivity in methanol-d4 (entries 3, 8-
11).
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b. Reactions in Trifluoroacetic Acid-d1. H/D exchange reactivity in trifluoroacetic acid-d1 is
shown in Table 2. Catalysts 1 (PMe3), 3 (NHC), and 4 (NHC) show similar TONs in
trifluoroacetic acid-d1 compared to the corresponding reaction in methanol-d4. In contrast,
complex 2, which contains weakly donating aqua ligands, exhibits poor activity in methanol-d4
(TON = 16.5(2)) but improved reactivity in trifluoroacetic acid-d1 (TON = 105(8), entry 3).
Similarly, the pyridine and pyridinium containing catalysts 6 and 7, when treated with AgOTf,
exhibit improved reactivity in trifluoroacetic acid-d1 (TON = 95(5) and 57(2) respectively)
compared to in methanol-d4 (TON = 3(0) and 3(2) respectively). It is also noteworthy that in
trifluoroacetic acid-d1, there is significant H/D exchange when AgOTf is employed as a catalyst
(44% deuterium incorporation after 24 h) and a small background reaction with the solvent in the
absence of a metal (6% deuterium incorporation after 24 h). This is not the case in methanol-d4
or acetic acid-d4.9
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Table 2. Results for catalytic H/D exchange reactions with complexes 1-7 in trifluoroacetic acid-
d1.
Entry Catalyst Additive TONb
1
2
3
4
5
1
1
2
3
3
None
159(2)
AgOTfc 146(2)
None
None
105(8)
18(2)
AgOTfc 51(1)
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None
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70(4)
7(3)
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AgOTfc 95(5)
None 10(3)
AgOTfc 57(2)
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a Reactions were run for 24 h with 25
equivalents of deuterium source to
C6H6. Reported turnover numbers
are the average of at least three trials
and error is reported as the standard
deviation of the mean. Turnover
numbers (TONs) are calculated as
moles of D incorporated per mole of
catalyst. Conditions: Benzene-d6 (42
μL, 0.475 mmol), trifluoroacetic
acid-d1 (11.9 mmol), and the
b
respective
(0.0095 mmol). Two equivalents of
AgOTf were added.
iridium(III)
catalyst
c
c. Reactions in acetic acid-d4. The data presented above shows that the ancillary ligand (L) in
the Cp*Ir(L) fragment significantly affects the TONs for catalytic H/D exchange reactions in
trifluoroacetic acid-d1 and methanol-d4. In marked contrast, this is not the case in acetic acid-d4.
Independently synthesized complexes 8-11 that incorporate acetate ligands in the primary
coordination sphere are depicted in Chart 2. As shown in Figure 2, regardless of the ancillary
ligands, all catalysts afforded approximately the same activity (TONs between 30 and 40) and
complexes 8-11 performed as effectively as complexes 1, 4, 6 and 7.
Chart 2. Acetate Containing Catalysts (8-11)
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Ir
Ir
OAc
OAc
OAc
OAc
L
L
L = PMe3, 9
L = NHC, 8
9
PF6
PF6
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Ir
Ir
O
O
L
L
O
O
L = NHC, 10
L = PMe3, 11
50
40
30
20
10
0
*1
4
*6
*7
8
9
10
11
Figure 2. Catalytic H/D exchange reactions with complexes 1, 4, 6, 7, 8, 9, 10 and 11 in acetic
acid-d4. Conditions: Reactions were run for 24 h with 25 equivalents of deuterium source to
C6H6. The reported turnover numbers are the average of at least three trials and error is reported
as the standard deviation of the mean. * 2 equivalents of AgOTf were added to the complex.
Mechanism for Catalytic H/D Exchange.
The H/D exchange data presented above suggests that different mechanisms for C-H
activation may be operational when different solvents/deuterium sources are employed, as well
as when the ancillary ligand L is varied. To investigate this possibility further, we examined the
mechanism of the catalytic H/D exchange reaction with catalyst 4. This catalyst was chosen
because: 1) its activity was amongst the highest of all the catalysts studied, 2) H/D exchange
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proceeded with this catalyst without the need for activation with AgOTf, and 3) high TONs were
achieved with this catalyst in all three deuterium sources.
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a.
Isotope Effects. The effect of isotopic substitution on the catalytic H/D exchange
reactions was first investigated. Isotope effects were determined by comparing the
turnover numbers for deuterium exchange into C6H6 (C-H activation) to turnover
numbers for proton incorporation into C6D6 (C-D activation).10 Turnover numbers
were obtained by GC/MS analysis of isotopologue concentrations. As shown in Table
3, the isotope effect varies significantly as a function of the solvent/deuterium source.
When the deuterium source/solvent is methanol-d4 or acetic acid-d4, a primary isotope
effect is observed (entries 1 and 2). In contrast, trifluoroacetic acid-d1 affords an
inverse isotope effect (entry 3). Similar isotope effects have been observed for other
catalysts and these data are presented in the Supporting Information.
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Table 3. Isotope effects for the catalytic deuterium exchange into benzene with a variety of
solvents for catalyst 4
Entry
Solventa
Isotope Effectb
3.8(2)
1
2
3
methanol
acetic acid
6.7(4)
trifluoroacetic acid
0.80(9)
a 25 equivalents of deuterium source to C6H6. Reported isotope effects were determined by
dividing the TON listed in Table 2 by the TON for the incorporation of protons into C6D6. All
TONs were determined by GC/MS.
b
b. Mechanism of H/D exchange in methanol-d4. The kinetics of the reaction catalyzed by
4 in CD3OD was next examined in more detail. As shown in Figure 3, the reaction shows a 1st
order dependence on the Ir catalyst 4 (Figure 3a) and saturation kinetics in [C6H6] (Figure 3b).11
A general mechanism that is consistent with the data is presented in Scheme 2 with the
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corresponding rate expression (assuming Michaelis Menten-type kinetics) depicted in equation 1.
For this mechanism, benzene, Ph-H, is activated by a transition metal complex, M, to generate
an Ir-phenyl complex, Ir-Ph. The Ir-Ph complex then reacts with the solvent, ROD, to form
deuterated product, Ph-D, and regenerate the starting Ir complex, M.12
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k
1
k
2
[Ph-H][M]
T
Rate =
(1)
k
-1[H+ ] + k
2
+ k [Ph-H]
1
0
-0.2
-0.4
-0.6
-0.8
a.
slope = 0.96(5)
R2 = 0.99
-1
0.6
0.8
1
1.2
1.4
1.6
log[4]
Figure 3. a) Plot of initial rate of deuterium incorporation versus [4] in methanol-d4 b) Plot of
turnover frequency versus [benzene] in methanol-d4. Conditions: (a) Ir catalyst (0.0024, 0.0028,
0.0095, 0.019 mmol), benzene (0.475 mmol), methanol-d4 (11.9 mmol) at 150 ºC for 0.5 h. (b) Ir
catalyst (0.0095 mmol), benzene (0.238, 0.475, 0.950, 1.68 mmol), methanol-d4 (11.9 mmol) at
150 ˚C for 0.5 h. Data are fit with nonlinear least-squares fitting to an equation describing
saturation in [benzene]: kobs = k2[benzene]/k´+[benzene] where k´ = (k-1[H+] + k2)/k1. Turnover
frequencies were determined by GC/MS.
Scheme 2. Proposed mechanism for the H/D exchange reaction of benzene in weakly and
moderately acidic solvents.
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k1
- H+
k2
Ir + Ph-H
Ir
Ir + Ph-D
+ RO-D
Ph
+ H+
k-1
M
Ir-Ph
M
9
c.
Mechanism of H/D exchange in trifluoroacetic acid-d1. A different mechanism
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appears to be operational in trifluoroacetic acid-d1. This hypothesis is based on the following
experimental observations:
1) Catalytic H/D exchange reactivity for complexes with weak/poor donor ligands is enhanced
in trifluoroacetic acid-d1.
2) Primary isotope effects are observed when the reactions are performed in methanol-d4 and
acetic acid-d4, while inverse isotope effects are observed in trifluoroacetic acid-d1.
3) Reactions performed in methanol-d4 incorporate deuterium at a significantly faster rate than
those performed in trifluoroacetic acid-d1. The reaction in methanol-d4 showed an exponential
appearance of the deuterated products and achieved the maximum turnovers in approximately
600 min (Figure S8).13 In contrast, the turnover numbers for the catalytic reaction performed in
trifluoroacetic acid-d1 increased at a significantly slower rate, and maximum turnovers were not
achieved even after 4 d (Supporting Information). The reaction without a catalyst progressed at
an even slower rate and again maximum turnovers were not reached after 4 d. These results
clearly demonstrate that H/D exchange proceeds in trifluoroacetic acid-d1 without the need for a
catalyst. However, the rate of H/D exchange appears to be enhanced in the presence of 4.
In trifluoroacetic acid-d1, the order with respect to the concentration of 4 was 0.49(4) (Figure
4),14 while the order with respect to the concentration of benzene was 0.88(9) (Figure 5).
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-0.1
-0.15
-0.2
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-0.25
-0.3
slope = 0.49(4)
R2 = 0.99
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-0.35
-0.4
-0.45
-0.5
0.3 0.4 0.5 0.6 0.7 0.8 0.9
1
1.1
log[4]
Figure 4. Plot of initial rate of deuterium incorporation versus [4] in trifluoroacetic acid-d1
-2.4
-2.6
-2.8
slope = 0.88(9)
-3
R2 = 0.98
-3.2
-3.4
-0.6
-0.4
-0.2
0
0.2
0.4
log[benzene]
Figure 5. Plot of initial rate of deuterium incorporation versus [benzene] in trifluoroacetic acid-
d1
A proposed mechanism for H/D exchange in trifluoroacetic acid-d1 that is consistent with
all of this data is depicted in Scheme 3. Interaction of the solvent with the transition metal center
results in the species M(TFA) and D+. In a second step, D+ interacts with benzene by an
electrophilic aromatic substitution (Ar-SE) mechanism with rate-determining formation of an
arenium cation, followed by loss of H+ and the formation of the deuterated product. According to
this mechanism, the role of the transition metal is to increase the Brønsted acidity of the solvent.
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Scheme 3. Proposed mechanism for H/D exchange in CF3CO2D
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KD
LnM(TFA)- + D+
LnM
CF3COOD
M
M(TFA)
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H
D
k1
+
Ph-H +
D
slow
H
D
k2
LnM(TFA)-
Ph-D + CF3COOH + LnM fast
+
M(TFA)
M
In order to further test the plausibility of an Ar-SE mechanism we examined the site-
selectivity of D incorporation into t-butyl benzene via 1H NMR spectroscopy (Scheme 4). If the
H/D exchange reaction proceeds by an Ar-SE mechanism, then preferential deuterium
incorporation at the ortho and para carbons should be observed because the t-butyl group is an
ortho and para director.
Scheme 4. Ir-catalyzed H/D exchange in tert-butylbenzene
Hortho
Hmeta
Hortho
Hmeta
Dortho
Dmeta
Dortho
Dmeta
2 mol% Ir
d-Source
150 ºC
Hpara
Dpara
d-Source = methanol-d4, triflouroacetic acid-d1
As shown in Table 4 when the reaction is performed in trifluoroacetic acid-d1 in the
absence of a catalyst (Entry 1), the site selectivity for deuterium incorporation into the ortho and
para positions of t-butyl benzene was consistent with an Ar-SE mechanism. When the reaction is
performed with catalyst 4, comparable site selectivity was observed (Entry 2). In contrast, when
the reaction was performed with 4 in methanol-d4 preferential deuterium incorporation into the
meta position was observed.15
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Table 4. Site-selectivity of deuterium incorporation (%) into the ortho, meta, and para
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6
positions of t-butyl benzene.
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Selectivitya
Entry
Catalyst
Solvent
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(ortho/meta/para)
2.0/1.0/2.3
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N/A
4
CF3CO2D
CF3CO2D
CD3OD
2.3/1.0/2.8
4
0.42/1.0/0.42
aDeuterium incorporation (%) was determined by H NMR spectroscopy with a 0.1 M DSS
internal standard in D2O (DSS = Sodium 4,4-Dimethyl-4-silapentane-1-sulfonate)
1
d. Mechanism of H/D exchange in acetic acid-d4.
As discussed above, when acetic acid-d4 was used as a solvent, TONs for the various catalysts
were essentially the same, regardless of the ancillary ligand. We hypothesize that this is because,
in all cases, the catalytically active species has incorporated an acetate ligand from the acetic
acid solvent. Importantly, the mechanism for C–H activation with complexes incorporating
acetate ligands has been extensively studied.2q, 2u, 16 In many of these cases, the rate determining
step for C–H activation is not C–H bond cleavage, but binding of the substrate to the metal
complex.17 This is because the acetate ligand has a strong propensity to coordinate to the metal
center in a bidentate fashion. Thus, C–H activation reactivity in these systems represents a subtle
balance between (i) the equilibrium constant for κ2 to κ1 isomerization of the acetate ligand
(which opens a site at the metal for C–H σ-complex formation) and (ii) the ability of the
carbonyl oxygen to deprotonate the coordinated C–H bond. We propose that these acetate ligand
effects are the predominant factor that affects catalyst activity in acetic acid-d4, and thus the
ancillary ligand L has minimal influence on extent of H/D exchange. This proposal is supported
by the H/D exchange reactivity described above (Figure 2) for Ir(III) acetate complexes 8-11
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(Chart 2).18 Significantly, catalysts 8-11 provided nearly identical results to catalysts 1, 4, 6 and 7
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with TONs between 30 and 40.19
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Conclusions
In summary, this study has important implications for the design of Cp*IrIII(L) complexes for
C-H activation/functionalization. First, the solvent dramatically influences the mechanism of
H/D exchange. We believe that organometallic mechanisms are occurring in acetic acid-d4 and
methanol-d4, while an Ar-SE mechanism is operating in trifluoroacetic acid-d1. The evidence
supporting these proposals is:
a) Primary isotope effects are observed in methanol-d4 and acetic acid-d4, while inverse
isotope effects are observed in trifluoroacetic acid-d1 (Table 3).
b) The rate of incorporation of deuterium is faster in methanol-d4 than in trifluoroacetic-d1.
H/D exchange in methanol-d4 resulted in maximum turnovers after ~ 600 min (kobs = 1.7(5) × 10-3
min-1). In contrast deuterium incorporation for the H/D exchange reaction in trifluoroacetic acid-
d1 did not achieve maximum turnovers even after 4 d (kobs = 3.3(7) × 10-4 min-1). Furthermore,
reactions performed without a catalyst displayed a similar time profile (kobs = 1.7(5) × 10-4 min-1).
Second, the ancillary ligand, L, also influences H/D exchange reactivity. The most active
catalysts in methanol-d4 contain strong donor ligands (PMe3 and NHC). For complexes with this
class of ligand, hydride species have been identified in catalytic H/D exchange reactions in this
solvent. In contrast, for complexes with moderate to weak donor ligands (aqua, pyridine,
pyridinium) no evidence for the formation of hydrides was observed. This difference in reactivity
may be due to the ability for the complex to form a hydride by β-hydride elimination from an Ir-
methoxy intermediate.
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In acetic acid-d4 the ancillary ligand L appears to have a minimal impact on H/D
exchange reactivity, as TONs of 30-40 are observed regardless of the ligand. In this solvent, C-H
activation is proposed to proceed by an acetate-assisted sigma bond metathesis mechanism. As a
result, we hypothesize that H/D exchange reactivity is influenced most significantly by the κ2 to
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κ1 isomerization of the acetate ligand and the ability of the carbonyl oxygen to deprotonate the
coordinated C–H bond.
The results presented herein suggest that the proper choice of solvent and ancillary ligand
could result in the rational design of new C-H functionalization catalysts that incorporate the
Cp*Ir(L) motif. The observation that complexes with strong donor ligands result in the formation
of Ir hydrides and that these species enable C-H activation in weakly acidic polar solvents such
as methanol-d4, is particularly intriguing and suggests that catalysts may be developed that take
advantage of these propensities.
EXPERIMENTAL SECTION
General Considerations. The complexes 1, 2, 3, 9, and 11 were prepared according to
published procedures.18, 20 Other reagents were purchased from commercial sources and used as
1
13
received. H and C NMR spectra were recorded on a Varian Mercury 400 MHz or a Varian
Mercury 300 MHz spectrometer at room temperature. 1H and 13C NMR chemical shifts are listed
in parts per million (ppm) and are referenced to residual protons or carbons of the deuterated
solvents, respectively. Mass spectrometry was performed by the North Carolina State University
Mass Spectroscopy Facility using an Agilent Technologies 6210LC-TOF mass spectrometer
(GC/MS). Elemental analyses were performed by Atlantic Microlabs, Inc. X-Ray
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crystallography was performed at the X-Ray Structural Facility of North Carolina State
University by Dr. Paul Boyle.
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H/D Exchange Reactions. Benzene (42 μL, 0.475 mmol), deuterated solvent (11.9 mmol),
and the respective iridium(III) catalyst (0.0095 mmol) were added to a ~3 mL Teflon sealed
storage tube. The Schlenk tube was placed in a temperature controlled oil bath set to 150 °C for
24 h. The reaction mixture was then cooled to room temperature and filtered through Celite.
Reactions in acidic solvents were quenched with sodium bicarbonate and filtered through Celite.
The resulting solution was then analyzed by GC/MS.
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Isotope Effect Studies. Benzene-d6 (42 μL, 0.475 mmol), solvent (11.9 mmol), and the
respective iridium(III) catalyst (0.0095 mmol) were added to a ~3 mL Teflon sealed storage tube.
The Schlenk tube was placed in a temperature controlled oil bath set to 150 °C for 24 h. The
reaction mixture was then cooled to room temperature and filtered through Celite. Reactions in
acidic solvents were quenched with sodium bicarbonate and filtered through Celite. The
resulting solution was then analyzed by GC/MS.
Time Profile Studies. Benzene (42 μL, 0.475 mmol), solvent (11.9 mmol), and the respective
iridium(III) catalyst (0.0095 mmol) were added to a ~3 mL Teflon sealed storage tube. The
Schlenk tube was placed a temperature controlled oil bath set to 150 °C. Aliquots were removed
from reaction mixture after various time intervals and analyzed by GC/MS.
Kinetic Studies in Methanol-d4. Benzene (10.5 μL, 0.119 mmol; 21 μL, 0.238 mmol; 42 μL,
0.475mmol; 84 μL, 0.950 mmol), methanol-d4 (480 μL, 11.9 mmol), and the respective
iridium(III) catalyst (0.0095 mmol) were added to a ~3 mL Teflon sealed storage tube. The
Schlenk tube was placed in a temperature controlled oil bath set to 150 °C for 0.5 h. The reaction
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mixture was then cooled to room temperature and filtered through Celite. The resulting solution
was then analyzed by GC/MS.
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Kinetic Studies in Acetic Acid-d4. Benzene (21 μL, 0.238 mmol; 42 μL, 0.475 mmol; 63 μL,
0.713 mmol; 84 μL, 0.950 mmol), acetic acid-d4 (680 μL, 11.9 mmol), and the respective iridium
(III) catalyst (0.0095 mmol) were added to a ~3 mL Teflon sealed storage tube. The Schlenk
tube was placed in a temperature controlled oil bath set to 150 °C for 0.5 h. The reaction mixture
was then cooled to room temperature, quenched with sodium bicarbonate, and filtered through
Celite. The resulting solution was then analyzed by GC/MS.
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Kinetic Studies in Trifluoroacetic Acid-d1. Benzene (21 μL, 0.238 mmol; 42 μL, 0.475
mmol; 84 μL, 0.950 mmol; 126 μL, 1.43 mmol), trifluoroacetic acid-d1 (680 μL, 11.9 mmol),
and the respective iridium (III) catalyst (0.0095 mmol) were added to a ~3 mL Teflon sealed
storage tube. The Schlenk tube was placed in a temperature controlled oil bath set to 150 °C for
0.5 h. The reaction mixture was then cooled to room temperature, quenched with sodium
bicarbonate, and filtered through Celite. The resulting solution was then analyzed by GC/MS.
Initial Rate of Deuterium Incorporation as a Function of [4] in Methanol-d4. Benzene (42
μL, 0.475 mmol), methanol-d4 (480 μL, 11.9 mmol), and 4 (1.8 mg, 0.0024 mmol; 3.6 mg,
0.0048 mmol; 7.2 mg, 0.0095 mmol; 14.4 mg, 0.019 mmol) were added to a ~3 mL Teflon
sealed storage tube. The tube was placed in a temperature controlled oil bath set to 150 °C for 15
min. The reaction was then cooled to room temperature and filtered through Celite. The
resulting solution was then analyzed by GC/MS. Initial rate data were obtained by dividing the
TONs obtained from the assay by time (15 min). A plot of log (initial rate) versus the log [4] was
linear (R2 = 0.99)
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Initial Rate of Deuterium Incorporation as a Function of [4] in Trifluoroacetic Acid-d1.
Benzene (42 μL, 0.475 mmol), trifluoroacetic acid-d1 (0.911 μL, 11.9 mmol) and 4 (1.8 mg,
0.0024 mmol; 3.6 mg, 0.0048 mmol; 7.2 mg, 0.0095 mmol; 14.4 mg, 0.019 mmol) were added to
a ~3 mL Teflon sealed storage tube. The tube was placed in a temperature controlled oil bath set
to 150 °C for 7 h. The reaction mixture was quenched with sodium bicarbonate and filtered
through Celite. The resulting solution was analyzed by GC/MS. Initial rate data were obtained
by dividing the TONs obtained from the assay by time (420 min). A plot of log (initial rate)
versus log [4] was linear.
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ASSOCIATED CONTENT
Supporting Information. Syntheses of complexes, spectra, kinetic data, X-ray experimental for
4. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: eaison@ncsu.edu.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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This work was supported by the NSF as part of the Center for Enabling New Technologies
through Catalysis (CENTC), CHE-0650456 and CHE-1205189. We thank Karen I. Goldberg, D.
Michael Heinekey and William D. Jones for helpful discussions.
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Cesar, V.; Gade, L. H.; Bellemin-Laponnaz, S., In RSC Catal. Ser., Diez-Gonzales, S., Ed. Royal
Society of Chemistry: 2011; Vol. 6, pp 228-251; (c) Hanasaka, F.; Fujita, K.-I.; Yamaguchi, R.
Organometallics 2006, 25, 4643-4647; (d) Feng, Y.; Jiang, B.; Boyle, P. A.; Ison, E. A.
Organometallics 2010, 29, 2857-2867; (e) Yung, C. M.; Skaddan, M. B.; Bergman, R. G. J. Am.
Chem. Soc. 2004, 126, 13033-13043.
(9) All entries that employ AgOTf were corrected according to reference 5d. The raw H/D
exchange data for all catalytic transformations with trifluoroacetic acid-d1 were corrected by
subtraction of the %deuterium incorporation observed in the background reaction between
trifluoroacetic acid-d1 and C6H6 in the presence of AgCl which is formed in situ when AgOTf is
added to a catalyst. Under the conditions for the catalytic reaction there is not a significant
amount of AgOTf present.
(10) The H/D exchange reaction is clearly complicated, involving many steps and many
transition states, thus our utilization of isotope effects here are just to show that the effect of
isotopic substitution is different in the different solvents for the H/D exchange reactions. We do
not presume to know the origin of these isotope effects i.e. whether they are kinetic isotope
effects or equilibrium isotope effects.
(11) The concentration of benzene in methanol may affect the dielectric constant. However,
curvature in the TOF vs [benzene] commences at concentrations much less than 1 M. At
concentrations such as these, the dielectric constant of the solvent is not expected to change
significantly. Further the trend in saturation is seen not only for catalyst 4 but several other
catalysts used in this study.
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(12) The elementary steps proposed for C-H activation in methanol are standard, (For a
discussion on mechanisms for C-H functionalization, see: Hartwig, J. F. Organotransition Metal
Chemistry: From Bonding to Catalysis; University Science Books: Mill Valley, CA, 2010; pp
825-826) i.e. an organometallic species activates benzene to form an Ir-Ph complex. This
complex then reacts with the deuterium source to generate the deuterated product. We do not
speculate on the exact nature of the organometallic species at this time nor do we speculate about
the nature of the C-H activation mechanism as we do not have any evidence to support these
claims and such a study is beyond the scope of this manuscript.
(13) After 600 min, the catalyst appears to be deactivated. However, thermal stability studies
of the catalyst in this solvent did not reveal any evidence of a new Ir species nor was there any
evidence of iridium black.
(14) To derive:
d[Ph-D]/dt = k1[Ph-H][D+ ]
Since [M(OTFA)] = [D+]
Then KD = [D+]2/[M]
KD[M]1/2 = [D+]
d[Ph-D]/dt = k1KD[Ph-H][M]1/2
(15) Reactions were performed in acetic acid-d4 as well. However, no H/D exchange was
observed with t-butyl benzene in this solvent.
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(16) (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem Rev 2010, 110, 624-655; (b)
Boutadla, Y.; Davies, D. L.; Jones, R. C.; Singh, K. Chem. Eur. J. 2011, 17, 3438-3448; (c)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174-238; (d) Guimond, N.;
Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2011, 133, 6449-6457; (e) Maleckis, A.; Kampf, J.
W.; Sanford, M. S. J. Am. Chem. Soc. 2013, 135, 6618-6625; (f) Boutadla, Y.; Al-Duaij, O.;
Davies, D. L.; Griffith, G. A.; Singh, K. Organometallics 2009, 28, 433-440; (g) Davies, D. L.;
Macgregor, S. A.; Poblador-Bahamonde, A. I. Dalton Trans. 2010, 39, 10520-10527.
(17) Boutadla, Y.; Davies, D. L.; Macgregor, S. A.; Poblador-Bahamonde, A. I. Dalton Trans.
2009, 38, 5887-5893.
(18) Isobe, K.; Bailey, P.M.; Maitlis P.M. J. Chem. Soc., Dalton Trans., 1981, 2003-2008.
(19) In order to test for heterogeneity, a mercury drop experiment was performed in this
solvent. No evidence for catalyst inhibition was observed.
(20) (a) Hetterscheid, D. G. H.; Reek, J. N. H. Chem. Commun. 2011, 47, 2712-2714; (b)
Xiao, X.-Q.; Jin, G.-X. J. Organomet. Chem. 2008, 693, 3363-3368; (c) Cayemittes, S.; Poth, T.;
Fernandez, M. J.; Lye, P. G.; Becker, M.; Elias, H.; Merbach, A. E. Inorg. Chem. 1999, 38,
4309-4316; (d) Ogo, S.; Makihara, N.; Watanabe, Y. Organometallics 1999, 18, 5470-5474.
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SYNOPSIS.
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2 mol% Ir
dn
d-Source
150 ºC
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d-Source = acetic acid-d4, methanol-d4, triflouroacetic acid-d1
4
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Methanol-d4
TON (24 h) = 79(5)
Isotope Effect (H/D) = 3.8(2)
OTf2
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Trifluoroacetic acid-d1
TON (24 h) = 70(4)
Isotope Effect (H/D) = 0.80(9)
Ir
OH2
OH2
N
N
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Acetic acid-d4
TON (24 h) = 28(3)
Isotope Effect (H/D) = 6.7(4)
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